1. Field of the Invention
The present invention is directed to a compound that is capable of inhibiting the enzyme, aminopeptidase P, whose natural substrate is bradykinin. The compound of the present invention is useful as a pharmaceutical agent because by inhibiting bradykinin degradation, the compound of the present invention allows bradykinin to exert its beneficial effects on the cardiovascular system (including decreasing blood pressure, dilating the coronary arteries, and providing protective effects on the heart during myocardial ischemia reperfusion injuries), to improve renal function, and to improve glucose tolerance and insulin-sensitivity. The present invention is also directed to a method for inhibiting bradykinin degradation in a mammalian patient.
2. Background of the Invention
Bradykinin (Bk) is a nine-amino acid peptide hormone which has recently been shown to have numerous beneficial effects on the cardiovascular system. These include decreased blood pressure, dilation of coronary arteries leading to increased blood flow to heart muscle, and direct protective effects on the heart during myocardial ischemia-reperfusion injuries. Bradykinin can also enhance renal function and improve glucose tolerance and insulin-sensitivity (2). See references as disclosed at the end of the Detailed Description (1-7). However, Bk is rapidly degraded in vivo. Almost complete inactivation of Bk occurs during a single circulation through the lung by peptidases located on the plasma membrane of vascular endothelial cells (8-10). One of the enzymes responsible for inactivation is angiotensin converting enzyme (ACE) (11).
Aminopeptidase P is known to cleave the N-terminal amino acid from peptides that have a prolyl residue in the second position (12, 14, 19). It has been suggested that membrane-bound aminopeptidase P may also have an important role in vivo in the pulmonary degradation of Bk (10-18) by cleaving its Arg.sup.1 -Pro.sup.2 bond. It has also been suggested that other peptidases may also play a role in Bk degradation (13). To date, studies to determine the role of aminopeptidase P in Bk metabolism in vivo have been hampered by the lack of a potent and specific inhibitor of aminopeptidase P. Accordingly, it is an object of the present invention to determine which enzymes, other than ACE, are involved in Bk degradation. It is a further object of this invention to discover and provide an inhibitor of aminopeptidase P. It is also an object of the present invention to provide a method for inhibiting bradykinin degradation in vivo.